PURPOSE Cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) with endocrine therapy (ET) improves progression-free survival (PFS) and overall survival (OS) in hormone receptor–positive (HR+), human epidermal growth factor receptor 2–negative (HER2–) metastatic breast cancer (MBC). Although preclinical and clinical data demonstrate a benefit in changing ET and continuing a CDK4/6i at progression, no randomized prospective trials have evaluated this approach. METHODS In this investigator-initiated, phase II, double-blind placebo-controlled trial in patients with HR+/HER2– MBC whose cancer progressed during ET and CDK4/6i, participants switched ET (fulvestrant or exemestane) from ET used pre-random assignment and randomly assigned 1:1 to the CDK4/6i ribociclib versus placebo. PFS was the primary end point, defined as time from random assignment to disease progression or death. Assuming a median PFS of 3.8 months with placebo, we had 80% power to detect a hazard ratio (HR) of 0.58 (corresponding to a median PFS of at least 6.5 months with ribociclib) with 120 patients randomly assigned using a one-sided log-rank test and significance level set at 2.5%. RESULTS Of the 119 randomly assigned participants, 103 (86.5%) previously received palbociclib and 14 participants received ribociclib (11.7%). There was a statistically significant PFS improvement for patients randomly assigned to switched ET plus ribociclib (median, 5.29 months; 95% CI, 3.02 to 8.12 months) versus switched ET plus placebo (median, 2.76 months; 95% CI, 2.66 to 3.25 months) HR, 0.57 (95% CI, 0.39 to 0.85); P = .006. At 6 and 12 months, the PFS rate was 41.2% and 24.6% with ribociclib, respectively, compared with 23.9% and 7.4% with placebo. CONCLUSION In this randomized trial, there was a significant PFS benefit for patients with HR+/HER2– MBC who switched ET and received ribociclib compared with placebo after previous CDK4/6i and different ET.

The emergence of Trop-2 as a therapeutic target has given rise to new treatment paradigms for the treatment of patients with advanced and metastatic breast cancer. Trop-2 is most highly expressed in triple negative breast cancer (TNBC), but the receptor is found across all breast cancer subtypes. With sacituzumab govitecan, the first FDA-approved, Trop-2 inhibitor, providing a survival benefit in patients with both metastatic TNBC and hormone receptor positive breast cancer, additional Trop-2 directed therapies are under investigation. Ongoing studies of combination regimens with immunotherapy, PARP inhibitors, and other targeted agents aim to further harness the effect of Trop-2 inhibition. Current investigations are also underway in the neoadjuvant and adjuvant setting to evaluate the therapeutic benefit of Trop-2 inhibition in patients with early stage disease. This review highlights the significant impact the discovery Trop-2 has had on our patients with heavily pretreated breast cancer, for whom few treatment options exist, and the future direction of novel Trop-2 targeted therapies.

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10588 Background: Testing for mutations in BRCA1 and BRCA2 is recommended for all women with ovarian cancer (OC), given important implications for treatment and prognosis. Despite this recommendation, studies show that only a small percentage of OC patients (pts) undergo genetic testing (GT). In this study, we evaluated rates of genetics referral, counseling and testing among OC pts at an academic medical center. Our goal was to identify factors associated with lower rates of GT. Given the large Black population at our center, we specifically wanted to evaluate the association between race and GT given limited existing data on this issue. Methods: Retrospective chart review was performed evaluating rates of referral and uptake for GT, and percentages of BRCA mutation carriers among pts with OC diagnosed and treated at Emory’s Winship Cancer Institute between 2008 and 2018. Associations between age, race, histology, family history (FH), performance status, provider characteristics and genetics referral and testing were evaluated using logistic regression models. Results: Of the 171 pts who met inclusion criteria, the majority were age 55 or older (62%) with high grade serous carcinoma (60.8%). Pts were predominantly Caucasian (59.4%), followed by Black (29.1%), Asian (10.3%) and Hispanic (1.2%). Overall, GT rates were low with 44.7% of pts referred for genetic counseling and 39.8% receiving testing. Among pts who did receive GT, the percentage of deleterious BRCA1 and BRCA2 mutations identified was 11% and 8.8% respectively. Variables correlating with higher likelihood of genetics discussion, referral and testing included serous histology (50% vs 23.9% non-serous, p < 0.001), Caucasian or Asian race (87.5% Asian, 58.8% Caucasian vs 42.2% Black, p = 0.003) and seeing a medical oncologist (67.5% vs 44.7% seeing gynecologic oncologist alone, p = 0.004). Notably, while fewer Black women were referred for GT (25.9% vs 74.1% Caucasian), those that did undergo GT were found to have higher rates of BRCA1 and BRCA2 mutations when compared to Caucasian pts (22.2% vs 8.2% BRCA1; 11.1% vs 6.0% BRCA2). Pts with a FH of OC were more likely to undergo GT (69.2% vs 37.9%, p = 0.027), and pts with a FH of breast cancer were more likely be referred for testing (57.1% vs 39.6%, p = 0.042), suggesting that FH impacted referral patterns. Conclusions: The rates of GT among OC pts at our institution were lower than expected despite the broad recommendation for GT in this population. It is imperative to improve access to GT for all OC pts regardless of FH, and in particular among Black pts given the higher rates of BRCA mutations in this population. Pts and providers must work together to overcome barriers to genetics referral and testing in order to improve GT rates and clinical outcomes. Further research is needed to design interventions that may help improve adherence to this important recommendation in the future.